CD146 mediates an E-cadherin-to-N-cadherin switch during TGF-β signaling-induced epithelial-mesenchymal transition
CD146 mediates an E-cadherin-to-N-cadherin switch during TGF-β signaling-induced epithelial-mesenchymal transition
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CD146 在 TGF-β 信号诱导的上皮间质转化过程中介导 E-钙粘蛋白到 N-钙粘蛋白的转换
DOI：
10.1016/j.canlet.2018.05.016
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发表时间：
2018-01-01
期刊：
影响因子：
9.7
通讯作者：
Yan, Xiyun
中科院分区：
文献类型：
--
作者：
Ma, Yanbin;Zhang, Haofeng;Yan, Xiyun
钙粘蛋白开关是上皮-间质转化（EMT）的启动因子，与肿瘤转移密切相关，但其机制尚不清楚。在这里，使用转化生长因子-g（TGF-β）诱导的EMT模型，我们提供了明确的证据表明，CD 146，在各种癌症中的表达和活性升高，是一个关键因素参与钙粘蛋白开关。我们发现，CD 146可以通过TGF-β信号转导诱导。此外，CD 146表达与STAT 3/Twist和ERK通路的活化水平正相关。CD 146/STAT 3/Twist级联的转录应答抑制E-钙粘蛋白表达，而CD 146/ERK级联增强N-钙粘蛋白表达。CD 146过表达也显著促进小鼠胚胎成纤维细胞（MEFs）和卵巢癌细胞中的EMT。在临床上，可检测到CD 146表达的卵巢癌患者的生存率明显低于CD 146表达阴性的患者。此外，CD 146缺陷型MEFs由于钙粘蛋白转换的逆转而表现出运动性降低，这强烈表明靶向CD 146是癌症治疗的潜在策略。因此，CD 146介导的E-cadherin-to-N-cadherin开关的调节提供了对EMT以及癌症转移的一般机制的深入了解。
Cadherin switch is an initiating factor of epithelial-mesenchymal transition (EMT) and is intimately correlated with cancer metastatic potential; however, its underlying mechanisms remain unclear. Here, using a transforming growth factor-g (TGF-beta)-induced EMT model, we provide explicit evidence that CD146, with elevated expression and activity in a variety of cancers, is a key factor involved in the cadherin switch. We show that CD146 can be induced by TGF-beta signaling. Moreover, CD146 expression is positively correlated with the activation levels of STAT3/Twist and ERK pathways. Transcriptional response of the CD146/STAT3/Twist cascade inhibits E-cadherin expression, whereas the CD146/ERK cascade enhances N-cadherin expression. CD146 overexpression also significantly promotes EMT in both mouse embryonic fibroblasts (MEFs) and ovarian cancer cells. Clinically, ovarian cancer patients with detectable CD146 expression had a significantly lower survival rate than that of patients without CD146 expression. Furthermore, CD146-deficient MEFs exhibited decreased motility as a result of reversion in this cadherin switch, strongly suggesting that targeting CD146 is a potential strategy for cancer treatment. Therefore, CD146-mediated regulation of the E-cadherin-to-N-cadherin switch provides an insight into the general mechanisms of EMT as well as cancer metastasis.